scholarly journals Bortezomib-induced heat shock response protects multiple myeloma cells and is activated by heat shock factor 1 serine 326 phosphorylation

Oncotarget ◽  
2016 ◽  
Vol 7 (37) ◽  
pp. 59727-59741 ◽  
Author(s):  
Shardule P. Shah ◽  
Ajay K. Nooka ◽  
David L. Jaye ◽  
Nizar J. Bahlis ◽  
Sagar Lonial ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Heat Shock ◽  
Heat Shock Response ◽  
Heat Shock Factor ◽  
Heat Shock Factor 1 ◽  
Myeloma Cells ◽  
Shock Response

Thermal acclimation changes DNA-binding activity of heat shock factor 1(HSF1) in the gobyGillichthys mirabilis: implications for plasticity in the heat-shock response in natural populations

2002 ◽  
Vol 205 (20) ◽  
pp. 3231-3240 ◽  
Author(s):  
Bradley A. Buckley ◽  
Gretchen E. Hofmann
Keyword(s):  
Gene Expression ◽  
Heat Shock ◽  
Heat Shock Response ◽  
Environmental Control ◽  
Heat Shock Factor ◽  
Thermal Acclimation ◽  
Model Systems ◽  
Threshold Temperature ◽  
Heat Shock Factor 1 ◽  
Shock Response

SUMMARYThe intracellular build-up of thermally damaged proteins following exposure to heat stress results in the synthesis of a family of evolutionarily conserved proteins called heat shock proteins (Hsps) that act as molecular chaperones, protecting the cell against the aggregation of denatured proteins. The transcriptional regulation of heat shock genes by heat shock factor 1(HSF1) has been extensively studied in model systems, but little research has focused on the role HSF1 plays in Hsp gene expression in eurythermal organisms from broadly fluctuating thermal environments. The threshold temperature for Hsp induction in these organisms shifts with the recent thermal history of the individual but the mechanism by which this plasticity in Hsp induction temperature is achieved is unknown. We examined the effect of thermal acclimation on the heat-activation of HSF1 in the eurythermal teleost Gillichthys mirabilis. After a 5-week acclimation period (at 13, 21 or 28°C) the temperature of HSF1 activation was positively correlated with acclimation temperature. HSF1 activation peaked at 27°C in fish acclimated to 13°C, at 33°C in the 21°C group, and at 36°C in the 28°C group. Concentrations of both HSF1 and Hsp70 in the 28°C group were significantly higher than in the colder acclimated fish. Plasticity in HSF1 activation may be important to the adjustable nature of the heat shock response in eurythermal organisms and the environmental control of Hsp gene expression.

During ischemia-reperfusion in rat kidneys, heat shock response is not regulated by expressional changes of heat shock factor 1

2000 ◽  
Vol 13 (4) ◽  
pp. 297-302 ◽  
Author(s):  
Ziya Akçetin ◽  
Reinhard Pregla ◽  
Dorothea Darmer ◽  
Hans-Jürgen Brömme ◽  
Jürgen Holtz
Keyword(s):  
Heat Shock ◽  
Heat Shock Response ◽  
Ischemia Reperfusion ◽  
Heat Shock Factor ◽  
Heat Shock Factor 1 ◽  
Shock Response ◽  
Rat Kidneys

Inhibition of Heat Shock Factor 1 (HSF1) Is More Effective At Sensitizing Myeloma Cells to Bortezomib Than Inhibition of Individual HSF1 Targets.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2953-2953
Author(s):  
Shardule P Shah ◽  
Sagar Lonial ◽  
Lawrence H. Boise
Keyword(s):  
Multiple Myeloma ◽  
Heat Shock ◽  
Heat Shock Response ◽  
Conflicts Of Interest ◽  
The United States ◽  
Myeloma Cell ◽  
Dependent Manner ◽  
Myeloma Cells ◽  
Shock Response ◽  
Induced Apoptosis

Abstract Abstract 2953 Multiple myeloma is a plasma cell disorder with an average incidence of 21,000 new cases per year in the United States. Recent advances in therapeutic approaches such as the use of proteasome inhibitors have resulted in a significant increase in the overall survival of myeloma patients. Myeloma cells maintain many of the characteristics of normal plasma cells, including constitutive immunoglobulin production and secretion, therefore management of ER stress plays a role in myeloma cell sensitivity to proteasome inhibition. However, myeloma cells also upregulate protective genes in response to the proteotoxic stress that can limit the therapeutic response. Previous groups have published on the importance of the heat shock response and the heat shock protein (HSP) family, supporting preclinical and clinical exploration of HSP inhibition in myeloma. Our group had interest in regulation of the HSP response and has evaluated the master regulator HSF1 as a potential therapeutic target. We found that siRNA-mediated silencing of HSF1 enhances bortezomib-induced apoptosis in a myeloma cell line. To define the effectors of the heat shock response important in regulating bortezomib response, we determined which heat shock response genes are induced by bortezomib in an HSF1-dependent manner. From a realtime PCR array of 84 HSP family genes, we found 21 genes that were induced greater than 2-fold by bortezomib. Of these 21 genes, 10 genes showed >50% reduction in HSF1-silenced cells. 7/10 genes were confirmed by independent qRT-PCR and western blot analysis. These genes include: CRYAB (alpha-crystallin B chain), DNAJB1 (HSP40 subfamily B), HSPA1A (HSP70-1A), HSPA1B (HSP70-1B), HSPB1 (HSP27), HSPH1 (HSP105/110), and HSP90AB1 (HSP90b1). To begin to determine which of these genes was important for the HSF1-dependent protective response we silenced the 7 genes individually and subsequently treated the cells with bortezomib. Surprisingly only 1 of the 7 genes silenced individually, DNAJB1, had an observable effect on bortezomib-induced death. However DNAJB1 silencing does not account for all the HSF1 activity as the increase in cell death due to bortezomib is only 48% of that observed with HSF1 silencing. Thus targeting HSF1 is more effective at sensitizing multiple myeloma cells to bortezomib-induced apoptosis than targeting individual HSPs. Moreover these data suggest that HSP90 inhibitors are functioning by inhibiting at least two members of this family to be effective as single agents. Therefore, while clinical trials for individual HSP and HSP in combination with bortezomib are being conducted, a more effective strategy for apoptosis induction is achieved through inhibition of HSP regulators such as HSF1 in combination with bortezomib. These results provide support for investigating HSP regulation in response to PI to increase the efficacy of myeloma therapy. Disclosures: No relevant conflicts of interest to declare.

Poly(ADP-ribosyl)ation regulates heat shock factor-1 activity and the heat shock response in murine fibroblasts

2006 ◽  
Vol 84 (5) ◽  
pp. 703-712 ◽  
Author(s):  
Silvia Fossati ◽  
Laura Formentini ◽  
Zhao-Qi Wang ◽  
Flavio Moroni ◽  
Alberto Chiarugi
Keyword(s):  
Heat Shock ◽  
Heat Shock Response ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Heat Shock Factor ◽  
Binding Motif ◽  
Heat Shock Factor 1 ◽  
Shock Response ◽  
Parp 1

Poly(ADP-ribose) polymerase-1 (PARP-1)-dependent poly(ADP-ribose) formation is emerging as a key regulator of transcriptional regulation, even though the targets and underlying molecular mechanisms have not yet been clearly identified. In this study, we gathered information on the role of PARP-1 activity in the heat shock response of mouse fibroblasts. We show that DNA binding of heat shock factor (HSF)-1 was impaired by PARP-1 activity in cellular extracts, and was higher in PARP-1−/− than in PARP-1+/+ cells. No evidence for HSF-1 poly(ADP-ribosyl)ation or PARP-1 interaction was found, but a poly(ADP-ribose) binding motif was identified in the transcription factor amino acid sequence. Consistent with data on HSF-1, the expression of heat-shock protein (HSP)-70 and HSP–27 was facilitated in cells lacking PARP-1. Thermosensitivity, however, was higher in PARP-1−/− than in PARP-1+/+ cells. Accordingly, we report that heat-shocked PARP-1 null fibroblasts showed an increased activation of proapoptotic JNK and decreased transcriptional efficiency of prosurvival NF-κB compared with wild-type counterparts. The data indicate that poly(ADP-ribosyl)ation finely regulates HSF-1 activity, and emphasize the complex role of PARP-1 in the heat-shock response of mammalian cells.

scholarly journals Identification of heat-inducible long noncoding RNA MALAT1-containing novel nuclear (HiNoCo) body

2021 ◽  
Author(s):  
Rena Onoguchi-Mizutani ◽  
Yoshitaka Kirikae ◽  
Yoko Ogura ◽  
Tony Gutschner ◽  
Sven Diederichs ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Response ◽  
Long Noncoding Rna ◽  
Mammalian Cells ◽  
Noncoding Rna ◽  
Heat Shock Factor ◽  
Nuclear Bodies ◽  
Cajal Body ◽  
Heat Shock Factor 1 ◽  
Shock Response

The heat shock response is critical for the survival of all organisms. Metastasis-associated long adenocarcinoma transcript 1 (MALAT1) is a long noncoding RNA localized in nuclear speckles, but its physiological role remains elusive. Here, we show that heat shock induces translocation of MALAT1 to a distinct nuclear body named heat shock-inducible noncoding RNA-containing nuclear (HiNoCo) body in mammalian cells. The MALAT1 knockout A549 cells showed reduced proliferation after heat shock. The HiNoCo body, formed by a nearby nuclear speckle, is distinct from any other known nuclear bodies, including the nuclear stress body, Cajal body, germs, paraspeckles, nucleoli, and promyelocytic leukemia body. The formation of HiNoCo body is reversible and independent of heat shock factor 1, the master transcription regulator of the heat shock response. Our results suggest the HiNoCo body participates in heat shock factor 1-independent heat shock responses in mammalian cells.

scholarly journals TG02 inhibits proteasome inhibitor–induced HSF1 serine 326 phosphorylation and heat shock response in multiple myeloma

2017 ◽  
Vol 1 (21) ◽  
pp. 1848-1853
Author(s):  
Shardule P. Shah ◽  
Ajay K. Nooka ◽  
Sagar Lonial ◽  
Lawrence H. Boise
Keyword(s):  
Multiple Myeloma ◽  
Heat Shock ◽  
Heat Shock Response ◽  
Proteasome Inhibitor ◽  
Proteasome Inhibition ◽  
Myeloma Cells ◽  
Key Points ◽  
Shock Response

Key Points Proteasome inhibition activates multiple kinases in myeloma cells resulting in the phosphorylation of p53, HSP27, c-JUN, and HSF1. TG02 inhibits proteasome inhibitor (PI)–induced HSF1 pS326, representing a novel mechanism for a TG02 and PI combination.

scholarly journals ATF1 Modulates the Heat Shock Response by Regulating the Stress-Inducible Heat Shock Factor 1 Transcription Complex

2014 ◽  
Vol 35 (1) ◽  
pp. 11-25 ◽  
Author(s):  
Ryosuke Takii ◽  
Mitsuaki Fujimoto ◽  
Ke Tan ◽  
Eiichi Takaki ◽  
Naoki Hayashida ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Response ◽  
Mammalian Cells ◽  
Target Genes ◽  
Acute Stress ◽  
Heat Shock Factor ◽  
Metabolic Adaptation ◽  
Heat Shock Factor 1 ◽  
Creb Binding Protein ◽  
Shock Response

The heat shock response is an evolutionally conserved adaptive response to high temperatures that controls proteostasis capacity and is regulated mainly by an ancient heat shock factor (HSF). However, the regulation of target genes by the stress-inducible HSF1 transcription complex has not yet been examined in detail in mammalian cells. In the present study, we demonstrated that HSF1 interacted with members of the ATF1/CREB family involved in metabolic homeostasis and recruited them on theHSP70promoter in response to heat shock. The HSF1 transcription complex, including the chromatin-remodeling factor BRG1 and lysine acetyltransferases p300 and CREB-binding protein (CBP), was formed in a manner that was dependent on the phosphorylation of ATF1. ATF1-BRG1 promoted the establishment of an active chromatin state andHSP70expression during heat shock, whereas ATF1-p300/CBP accelerated the shutdown of HSF1 DNA-binding activity during recovery from acute stress, possibly through the acetylation of HSF1. Furthermore, ATF1 markedly affected the resistance to heat shock. These results revealed the unanticipated complexity of the primitive heat shock response mechanism, which is connected to metabolic adaptation.

scholarly journals Heat shock factor 1 induces crystallin-αB to protect against cisplatin nephrotoxicity

2016 ◽  
Vol 311 (1) ◽  
pp. F94-F102 ◽  
Author(s):  
Qiang Lou ◽  
Yanzhong Hu ◽  
Yuanfang Ma ◽  
Zheng Dong
Keyword(s):  
Heat Shock ◽  
Heat Shock Response ◽  
Heat Shock Factor ◽  
Renal Tubular Cell ◽  
Heat Shock Factor 1 ◽  
Cytochrome C Release ◽  
Tubular Cells ◽  
Cisplatin Nephrotoxicity ◽  
Shock Response ◽  
Induced Apoptosis

Cisplatin, a wildly used chemotherapy drug, induces nephrotoxicity that is characterized by renal tubular cell apoptosis. In response to toxicity, tubular cells can activate cytoprotective mechanisms, such as the heat shock response. However, the role and regulation of the heat shock response in cisplatin-induced nephrotoxicity remain largely unclear. In the present study, we demonstrated the induction of heat shock factor (Hsf)1 and the small heat shock protein crystallin-αB (CryAB) during cisplatin nephrotoxicity in mice. Consistently, cisplatin induced Hsf1 and CryAB in a cultured renal proximal tubular cells (RPTCs). RPTCs underwent apoptosis during cisplatin treatment, which was increased when Hsf1 was knocked down. Transfection or restoration of Hsf1 into Hsf1 knockdown cells suppressed cisplatin-induced apoptosis, further supporting a cytoprotective role of Hsf1 and its associated heat shock response. Moreover, Hsf1 knockdown increased Bax translocation to mitochondria and cytochrome c release into the cytosol. In RPTCs, Hsf1 knockdown led to a specific downregulation of CryAB. Transfection of CryAB into Hsf1 knockdown cells diminished their sensitivity to cisplatin-induced apoptosis, suggesting that CryAB may be a key mediator of the cytoprotective effect of Hsf1. Taken together, these results demonstrate a heat shock response in cisplatin nephrotoxicity that is mediated by Hsf1 and CryAB to protect tubular cells against apoptosis.

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